This proposed Center grant application is for a 5-year competing renewal (A1) of the University of Washington Superfund Research Program (SRP). The overarching theme of the program is to investigate the mechanisms and ramifications of metal neurotoxicity in humans and aquatic species, and develop biomarkers based upon this understanding. These biomarkers may be predictive of (a) exposures to neurotoxic agents, (b) early indicators of neurotoxic injury at the cellular and organismal levels, and/or (c) genetic determinants that underlie unusual susceptibility to environmental neurotoxicants. The focus is on metal neurotoxicity, including those metals that commonly occur at Superfund hazardous waste sites for which there are important data gaps impeding the full understanding of their effects on human and ecological health. These data gaps include an understanding of mechanisms of toxicity, inter-individual or gender susceptibility, and biogeochemical factors that govern their environmental fate. The program will include five research projects (two environmental science and three biomedical projects), one of which (Project 2) is a new biomedical project since our 2013 A0 submission. The research includes investigations of (1) mechanisms and biomarkers of metal olfactory injury to Pacific salmon, with a primary focus on Cd; (2) cellular and molecular mechanisms of Cd-mediated neurotoxicity in rodents and humans, including effects on olfaction and cognition; (3) the role of paraoxonases as modifiers of Cd, Mn, and pesticide neurotoxicity in animal models and humans; (4) olfactory, motor, and cognitive effects from environmental exposure to manganese in a South African community living near a smelter; and (5) biogeochemistry and bioavailability of As in an urbanized lake system in Washington State. In accordance with the strategic goals of the SRP and in response to the 2013 reviews, this team has retained the strengths and theme of the UW SRP while making substantive changes to address weaknesses. The projects include key collaborators with other projects and cores, and thus each project is interdisciplinary in nature. The program includes a Training Core that is multi- and interdisciplinary, and will support pre-doctoral trainees. The Research Translation Core will continue to ensure timely and appropriate communication of our research findings to NIEHS and other appropriate stakeholders, partner effectively with agencies, identify potential patents, and develop and support translation opportunities with other end-users of our scientific findings. The Community Engagement Core will build upon existing partnerships and expand partnerships with other communities, such as those directly affected by the toxicants under study, and with other community groups that have concerns about environmental toxicants. The Administrative Core will stimulate interactions among projects and cores, ensure communication with NIEHS and other governmental agencies, oversee personnel and budgetary matters, and organize meetings and interactions with the External Advisory Board.